Alcohol Dependence (AD) is a major public health problem. Prior research demonstrates that genetic factors play a critical etiologic role in AD. The goal of this project is to identify specific susceptibility loci (SL) which impact on risk for AD. This proposal builds on the achievements of our ongoing Irish Affected Sib-Pair Study of Alcohol Dependence (IASPSAD) and those of other VCU-ARC component groups. During two previous funding periods, we 1) completed collections of a large affected sibling pair and control samples for AD in Ireland, 2) completed and analyzed a genome scan for AD, AD symptoms and other alcohol-related phenotypes (ARPs) and 3) have begun to test physiological and positional candidate genes: we have screened 122 genes using the NIAAA developed addictions array, completed 439 markers under our chromosome 4 linkage peak and completed a pooled genome wide association (GWA) for AD. We have produced strong evidence for association between AD and ZNF699 a human homolog of the Drosophila gene hangover. This application for a P20 Center Developmental Project grant has 4 specific aims: i) to comprehensively screen genes and ESTs for association with AD and ARPs in a region of chromosome 1 showing linkage evidence to both initial sensitivity and tolerance in our sample of 562 genetically independent cases drawn one per family from the sib-pair sample and 569 controls, using information-tagging single nucleotide polymorphisms (SNPs); ii) to assess in our human sample up to two selected and prioritized loci per year suggested by work in other organisms from other VCU-ARC component groups (mouse, c. elegans, drosophila) or the literature, and to similarly contribute associated human loci as candidates for further assessment in the model organisms in use by the other VCU-ARC component groups; iii) to use the data from these studies to empirically assess the performance of the gene selection and prioritization approaches developed by the VCU-ARC Bioinformatics Core, and to further develop the capacities of the selection and prioritization approach; iv) to assess, in secondary analyses, the effects of validated loci on other phenotypes for which data is available in the proposed sample, including other aspects of AD, nicotine dependence, illicit drug dependence, depression and conduct disorder, in order to clarify the phenotypic spectrum.